Obesity is a metabolic disorder characterized by excessive accumulation of fat stores in adipose tissue. Obesity is often associated with various pathological conditions or with risks of developing such conditions, e.g., cardiovascular disease, diabetes, cancer, hypertension, among others. In morbid obesity, the most effective method to achieve prolonged weight loss is via surgical intervention (1,2,3). One of the effective operations is the Roux-en-Y gastric bypass (RYGB), which produces durable weight loss. This operation is based on two principles: 1) creating a small gastric pouch to physically limit the size of a meal and thereby induce early satiety, and 2) inserting a short Roux-en-Y alimentary limb of distal small bowel, anastomosed to stomach and to proximal small bowel, to form a short common channel in which food from the pouch mixes with biliary-pancreatic digestive juices (4). The resulting anatomy of the RYGB reduces the amount of food that can be consumed, digested and absorbed, inducing prolonged weight loss (1,2,3). It is axiomatic that the RYGB operation in morbidly obese patients induces weight loss because of the mechanical restriction of the small gastric pouch and because of varying degrees of sub-clinical malabsorption (2,5,6). This notion was strengthened by an early study of eating patterns in 80 patients done 6, 12 and 24 months after RYGB (7). A significant reduction occurred in the amount of food eaten and in the frequency of eating. The authors concluded that gastric bypass “may have had an effect on digestion and absorption as well as the mechanical impairment of food intake secondary to the small gastric pouch”.
To understand the mechanisms whereby RYGB induced weight loss, a RYGB model in diet-induced obese Sprague-Dawley rats was developed (6,8,9). Eating patterns were measured using an Automated Computerized Rat Eater Meter. It was reported that meal size (Mz) is significantly smaller in RYGB than in sham operated (SO) obese control rats (6,8). Contrary to the usual physiological response, when MZ was decreased a compensatory increase in meal number (MN) occurred to maintain daily food intake (FI) constant (i.e. FI=MZ×MN) (10), a decrease in MN after RYGB occurred resulting in a net decrease in food intake contributing to weight loss (6,8,9). Since specific nuclei in the hypothalamus regulate MZ and MN, these primary food intake and energy regulating hypothalamic nuclei were also examined in the rat, after RYGB induced weight loss. It was reported that food intake and energy regulating genes are down regulated (12). In a more recent immunohistochemical study, it was demonstrated that clinically relevant food intake neuromediators were reduced after RYGB (11,12,13). The results of these studies suggest that the hypothalamus, which regulates GI hormone secretion via efferent vagal and sympathetic fibers to the GI tract, as well as via hypothalamic neuro-pituitary secretions of hormone precursor, plays a contributory role in decreasing food intake after RYGB. These data, together with both human and rat data, consistently show resolution of type 2 diabetes after RYGB, further suggesting that a hormonal component plays a contributory role in reducing food intake and facilitate protracted weight loss after RYGB (14).
There remains a need for effective compositions and methods for regulating body weight and for treating conditions associated with obesity.